Maternal pre-pregnancy/early-pregnancy smoking and risk of congenital heart diseases in offspring: A prospective cohort study in Central China

Background Prior studies suggested that maternal smoking before and during pregnancy could be associated with increased risks of congenital heart diseases (CHDs) in offspring. However, the results were inconsistent, and the existence of a causal relationship was not confirmed. Our study aimed to estimate the associations of maternal active and passive smoking during the pre-pregnancy/early-pregnancy period with CHDs as well as its common phenotypes in offspring. Methods This study was based on data from a prospective cohort study conducted in Central China. A total of 49 158 eligible pregnant women between the 8th and 14th weeks of gestation were invited to join the cohort and were planned to be followed up until 3 months postpartum. The exposure of interest was maternal smoking status, including active and passive smoking status in 3 months before pregnancy as well as in early pregnancy. Self-reported maternal smoking status was ascertained via an in-person interview after recruitment. CHDs were diagnosed by pediatric cardiologists and classified according to ICD-10. Multivariable Poisson regression models were used to estimate the relative risks (RRs) with 95% confidence intervals (CIs) of all CHDs and their common phenotypes associated with maternal smoking status, adjusting for potential confounding factors identified by directed acyclic graphs. Results CHDs were diagnosed in 564 children. After adjusting for potential confounding factors and comparing with the unexposed groups, CHDs incidence was 165% higher (adjusted RR = 2.65; 95% CI = 1.76-3.98) in offspring exposed to maternal active smoking in 3 months before pregnancy, 69% higher (adjusted-RR = 1.69; 95% CI = 1.39-2.05) in offspring exposed to maternal passive smoking in 3 months before pregnancy, 133% higher (adjusted RR = 2.33; 95% CI = 1.46-3.70) for offspring exposed to maternal active smoking in early pregnancy, and 98% higher (adjusted-RR = 1.98; 95% CI = 1.56-2.51) for offspring exposed to maternal passive smoking in early pregnancy. More specifically, the offspring exposed to maternal active smoking in early pregnancy had the highest risk of Tetralogy of Fallot (adjusted RR = 9.84; 95% CI = 2.49-38.84). These findings were recapitulated in analyses that further adjusted for other behaviour variables apart from the characteristic being assessed and were also confirmed by sensitivity analyses. Conclusions Our findings add to the existing body of evidence that implicates maternal pre-pregnancy/early-pregnancy smoking as a significant risk factor for CHDs and their select phenotypes.


Online Supplementary Document
Figure S1 Directed acyclic graph for the association between maternal active smoking in 3 months before pregnancy and risk of CHDs in offspring.

Figure S2
Directed acyclic graph for the association between maternal passive smoking in 3 months before pregnancy and risk of CHDs in offspring.

Figure S3
Directed acyclic graph for the association between maternal active smoking in early pregnancy and risk of CHDs in offspring.

Figure S4
Directed acyclic graph for the association between maternal passive smoking in early pregnancy and risk of CHDs in offspring.

Figure S5
The risks of CHDs in offspring of pregnant women with active smoking or passive smoking in 3 months before pregnancy after excluding pregnant women whose children had non-cardiac defects.

Figure S6
The risks of CHDs in offspring of pregnant women with active smoking or passive smoking in early pregnancy after excluding pregnant women whose children had non-cardiac defects.

Figure S1
Directed acyclic graph for the association between maternal active smoking in 3 months before pregnancy and risk of CHDs in offspring.
Minimal sufficient adjustment sets for estimating the effect of maternal active smoking in 3 months before pregnancy on offspring CHDs: age, ethnicity, educational level, parity, history of adverse pregnancy outcomes, and pre-pregnancy BMI.

Figure S2
Directed acyclic graph for the association between maternal passive smoking in 3 months before pregnancy and risk of CHD in offspring.
Minimal sufficient adjustment sets for estimating the effect of maternal passive smoking in 3 months before pregnancy on offspring CHD: age, ethnicity, educational level, parity, and history of adverse pregnancy outcomes.

Figure S3
Directed acyclic graph for the association between maternal active smoking in early pregnancy and risk of CHD in offspring.
Minimal sufficient adjustment sets for estimating the effect of maternal active smoking in early pregnancy on offspring CHD: age, ethnicity, educational level, model of conception, parity, history of adverse pregnancy outcomes, pre-pregnancy BMI, active smoking in 3 months before pregnancy, passive smoking in 3 months before pregnancy, and alcohol consumption in 3 months before pregnancy.

Figure S4
Directed acyclic graph for the association between maternal passive smoking in early pregnancy and risk of CHD in offspring.
Minimal sufficient adjustment sets for estimating the effect of maternal passive smoking in early pregnancy on offspring CHD: age, ethnicity, educational level, model of conception, parity, history of adverse pregnancy outcomes, pre-pregnancy BMI, active smoking in 3 months before pregnancy, and passive smoking in 3 months before pregnancy.

Figure S5
The risks of CHD in offspring of pregnant women with active smoking or passive smoking in 3 months before pregnancy after excluding pregnant women whose children had non-cardiac defects. A) Model 1 was a crude model without any variable adjusted; model 2 adjusted for age, ethnicity, educational level, parity, history of adverse pregnancy outcomes, and pre-pregnancy BMI; model 3 adjusted for age, ethnicity, educational level, parity, history of adverse pregnancy outcomes, pre-pregnancy BMI, passive smoking in 3 months before pregnancy, and alcohol drinking in 3 months before pregnancy. B) Model 1 was a crude model without any variable adjusted; model 2 adjusted for age, ethnicity, educational level, parity, and history of adverse pregnancy outcomes; model 3 adjusted for age, ethnicity, educational level, parity, history of adverse pregnancy outcomes, active smoking in 3 months before pregnancy, and alcohol drinking in 3 months before pregnancy.

Figure S6
The risks of CHD in offspring of pregnant women with active smoking or passive smoking in early pregnancy after excluding pregnant women whose children had non-cardiac defects. A) Model 1 was a crude model without any variable adjusted; model 2 adjusted for age, ethnicity, educational level, model of conception, parity, history of adverse pregnancy outcomes, pre-pregnancy BMI, active smoking in 3 months before pregnancy, passive smoking in 3 months before pregnancy, and alcohol consumption in 3 months before pregnancy; model 3 adjusted for age, ethnicity, educational level, model of conception, parity, history of adverse pregnancy outcomes, pre-pregnancy BMI, active smoking in 3 months before pregnancy, passive smoking in 3 months before pregnancy, alcohol consumption in 3 months before pregnancy, passive smoking in early pregnancy, and alcohol drinking in early pregnancy. B) Model 1 was a crude model without any variable adjusted; model 2 adjusted for age, ethnicity, educational level, model of conception, parity, history of adverse pregnancy outcomes, pre-pregnancy BMI, active smoking in 3 months before pregnancy, and passive smoking in 3 months before pregnancy; model 3 adjusted for age, ethnicity, educational level, model of conception, parity, history of adverse pregnancy outcomes, pre-pregnancy BMI, active smoking in 3 months before pregnancy, passive smoking in 3 months before pregnancy, active smoking in early pregnancy, and alcohol drinking in early pregnancy.